Validation of a single-pass surgical trajectory to enable AAV2-hAADC infusion into brainstem and mid-brain in nonhuman primate

项目摘要/摘要 芳香族L氨基酸脱羧酶缺乏症是一种罕见的儿童遗传性疾病，其突变 在DOPA脱羧酶基因(DDC)中，导致无功能的AADC酶导致消融 多巴胺和5-羟色胺合成。受影响的儿童会出现明显的运动症状，包括运动不足， 低眼压、眼肌危象和肌张力障碍，以及情绪不稳定、睡眠障碍和认知 减损。患者从目前可用的医疗疗法中几乎没有获得症状方面的好处。我们的长期合作 目标是提供一种治疗方法，通过以下方式消除这种疾病的神经体征和症状 局部输注编码人AADC的病毒载体(AAV2)提高AADC水平 大脑中的核团。在我们目前的探索性临床研究(NCT02852213)中，我们已经治疗了9名患者 单次双侧黑质前区AADC缺乏症恢复正常多巴胺合成 在基底节和边缘系统。来自队列1和队列2的初步评估证明了这一点 手术后一个半月左右，只有轻微的一过性运动障碍是安全的。已标记 眼科危象的减少或消除已被观察到。生化分析显示， 多巴胺代谢产物高香草酸(HVA)，3-羟甲基多巴(3-OMD)略有减少，而5-羟色胺 所有患者的代谢产物5-羟基吲哚乙酸(5-HIAA)均保持不变。目前，对这些问题的分析 分别在术后24个月和12个月进行的队列研究也表明，没有不良事件或 与手术过程或载体有关的严重不良事件。 目前的建议试图在非人类灵长类动物中积累安全数据，在这些数据中，一根插管就能通过 使载体能够传递到5-羟色胺能核和去甲肾上腺素能核以及当前的多巴胺能核。 这项研究的数据将用于提交新的IND，并为这一新程序招募更多的患者。 在我们看来，拟议的研究将对公众健康产生重大影响。虽然AADC缺陷是 这是一种罕见的儿科疾病，在患者的一生中，照顾者的负担和社会的代价都很大 提到病人自己的困境。从更广泛的意义上讲，这样的项目将继续加强 我们治疗遗传性神经疾病的能力。

PROJECT SUMMARY/ABSTRACT Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric genetic disorder in which mutations in the DOPA decarboxylase gene (DDC) result in a non-functional AADC enzyme that causes the ablation of dopamine and serotonin synthesis. Affected children suffer prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises and dystonia, as well as emotional lability, sleep disturbance and cognitive impairment. Patients derive little symptomatic benefit from currently available medical therapies. Our long-term goal is to provide a therapeutic approach to eliminate the neurological signs and symptoms of the disease by increasing the AADC levels via localized infusion of a viral vector (AAV2) encoding human AADC into affected nuclei in the brain. In our current exploratory clinical study (NCT02852213), we have treated 9 patients with AADC deficiency with a single bilateral infusion into the pre-nigral region to restore normal dopamine synthesis in the basal ganglia and limbic system. Preliminary evaluations from cohorts 1 and 2 have proven this approach to be safe with only mild and transient dyskinesia about one month and a half after surgery. Marked reduction or elimination of oculogyric crises has been observed. Biochemical analyses showed an increase in dopamine metabolite homovanillic acid (HVA), a slight reduction of 3-oxymethyldopa (3-OMD) while serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) remained unchanged in all patients. Currently, analyses of these cohorts, 24 and 12 months after surgery respectively, also showed that there have been no adverse events or serious adverse events related to the surgical procedure or the vector. The present proposal seeks to accumulate safety data in nonhuman primates in which a single cannula pass will enable vector delivery into serotonergic and noradrenergic nuclei as well as the current dopaminergic nuclei. Data from this study will be used to submit a new IND and recruit more patients for this new procedure. In our view, the proposed research will have a significant impact on public health. Although AADC deficiency is a rare pediatric disease, the burden to caregivers and the cost to society is large over the life of the patients not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases.